Givinostat HCl monohydrate (ITF-2357; Gavinostat))

Alias: ITF 2357; ITF2357; ITF-2357; Givinostat; gavinostat; ITF2357 HCl; ITF2357 hydrochloride; Givinostat HCl
Cat No.:V0289 Purity: ≥98%
Givinostat (formerly ITF2357; Gavinostat)is a potent andorally bioavailable inhibitor of both class I and class II histone deacetylase (HDAC) with potential anticancer activity.
Givinostat HCl monohydrate (ITF-2357; Gavinostat)) Chemical Structure CAS No.: 732302-99-7
Product category: HDAC
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Givinostat HCl monohydrate (ITF-2357; Gavinostat)):

  • Givinostat HCl
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Purity & Quality Control Documentation

Purity: ≥98%

Purity: ≥98%

Purity: ≥98%

Purity: ≥98%

Product Description

Givinostat (formerly ITF2357; Gavinostat) is a potent and orally bioavailable inhibitor of both class I and class II histone deacetylase (HDAC) with potential anticancer activity. It inhibits HDAC with IC50 values for HDAC1 and HDAC3 of 198 and 157 nM, respectively.In vitro, JAKEV617F-bearing progenitor cells from chronic myeloproliferative neoplasms efficiently inhibit the formation of hematopoietic colonies by glinostat.

Biological Activity I Assay Protocols (From Reference)
Targets
hHDAC3 ( IC50 = 157 nM ); hHDAC1 ( IC50 = 198 nM ); hHDAC11 ( IC50 = 292 nM ); hHDAC6 ( IC50 = 315 nM ); hHDAC2 ( IC50 = 325 nM ); hHDAC10 ( IC50 = 340 nM ); hHDAC7 ( IC50 = 524 nM ); hHDAC5 ( IC50 = 532 nM ); hHDAC9 ( IC50 = 541 nM ); hHDAC8 ( IC50 = 854 nM ); hHDAC4 ( IC50 = 1059 nM ); HD1-B ( IC50 = 7.5 nM ); HD1-A ( IC50 = 16 nM ); HD2 ( IC50 = 10 nM )
ln Vitro

In vitro activity: ITF2357 inhibits the release of TNFα, IL-1α, IL-1β, and IFNγ in LPS-stimulated cultured human peripheral blood mononuclear cells (PBMCs), with an IC50 of 10–25 nM, respectively. ITF2357, independent of decreased IL-1 or TNFα, reduces IFNγ and IL-6 production with an IC50 of 12.5–25 nM by combining IL–12 and IL–18. [1] RPMI8226, NCI-H929, JJN3, KMS 11, KMS 12, KMS 18, and KMS 20 are examples of multiple myeloma (MM) cell lines that ITF2357 is cytotoxic in; the IC50 for AML cell lines (HL-60, THP-1, U937, KASUMI, KG-1, and TF-1) is 200 nM. ITF2357 downmodulates Bcl-2 and Mcl-1, upregulates p21, and activates the intrinsic apoptotic pathway. ITF2357 reduces mesenchymal stromal cells' (MSCs) ability to produce IL-6, VEGF, and IFNγ by 80–95%. [2] ITF2357 promotes the survival of β-cells in inflammatory environments. ITF2357 increases islet cell viability, improves insulin secretion, inhibits MIP-1α and MIP-2 release, lowers NO production, and lowers apoptosis rates at concentrations of 25 and 250 nM. [3]

ln Vivo
ITF2357 (1–10 mg/kg) significantly lowers LPS-induced serum TNFα and IFNγ levels by over 50%. ITF2357 does not inhibit the release of anti-CD3-induced cytokines from mouse circulation-derived PBMCs in mice. ITF2357 (1 or 5 mg/kg) has been shown to significantly reduce liver damage in hepatitis induced by concanavalin A.[1] When severe combined immunodeficient mice are injected with the AML-PS in vivo passaged cell line, ITF2357 (10 mg/kg) considerably increases their survival time.[2] ITF2357 (10 mg/kg) reduces lesion volume, induces glial apoptosis, improves neurobehavioral recovery, and lessens neuronal degeneration in a mouse model of closed head injury (CHI).[4]
Enzyme Assay
The procedure for the assay involves mixing the crude cellular extract (5 μL) with 100 μL substrate (2×105 cpm), 40 μL buffer (50 mM Tris-HCl, pH 8.0, 750 mM NaCl, 5 mM PMSF, 50% glycerol), and 95 μL distilled water. To check for HDAC inhibition, add 50 μL of ITF2357. After the mixture has been incubated for a full night at room temperature, 50 μL of a solution made of 259 μL 37% HCl, 28 μL acetic acid, and 1 mL distilled water is added to quench the reaction. The organic extraction method is used to separate the [3H]acetyl residues that are released from the substrate. A beta-counter is used to measure radioactivity after adding 200 μL of the organic phase to standard scintillation fluid. By measuring the difference between the radioactivity of the inhibitor-containing samples and the control sample that only contained cellular crude extract, one can determine the concentration of HDACs that inhibits 50% of the control activity.
Cell Assay
The isolated PBMCs are cleaned, then resuspended at 5×106/mL in RPMI with 5% FCS, transferred to a 50-mL conical polypropylene tube, and kept at 4 °C for the night. A 96-well flat microtiter plate is filled with 100 μL of PBMCs after they have been resuspended the previous morning. The plates are then incubated at 37 °C for an hour after adding ITF2357 for the inhibition studies. The cells are then stimulated with LPS or other stimulants in a final volume of 200 μL per well. After being incubated for 24 hours at 37 °C, the supernatants are removed and frozen at -80 °C until they are tested for cytokines.
Animal Protocol
Mice: For a minimum of five days prior to usage, C57BL/6 mice are kept in the animal facility. Givinostat (ITF2357) is injected intraperitoneally for the comparison study, and it is also given orally at a dose of 10 mg/kg. LPS from Salmonella typhimurium is administered intraperitoneally to the animals at a dose of 2.5 mg/kg one hour after the compounds are administered. Serum is collected and kept at -80°C until further examination of cytokine production, and mice are sacrificed 90 minutes after the LPS treatment.
References

[1]. Mol Med . 2005 Jan-Dec;11(1-12):1-15.

[2]. Leukemia . 2007 Sep;21(9):1892-900.

[3]. Mol Med . 2011 May-Jun;17(5-6):369-77.

[4]. FASEB J . 2009 Dec;23(12):4266-75.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C24H27N3O4.HCL.H2O
Molecular Weight
475.97
Exact Mass
475.19
Elemental Analysis
C, 60.56; H, 6.35; Cl, 7.45; N, 8.83; O, 16.81
CAS #
732302-99-7
Appearance
White to beige solid powder
SMILES
CCN(CC)CC1=CC2=C(C=C1)C=C(C=C2)COC(=O)NC3=CC=C(C=C3)C(=O)NO.O.Cl
InChi Key
FKGKZBBDJSKCIS-UHFFFAOYSA-N
InChi Code
InChI=1S/C24H27N3O4.ClH.H2O/c1-3-27(4-2)15-17-5-7-21-14-18(6-8-20(21)13-17)16-31-24(29)25-22-11-9-19(10-12-22)23(28)26-30;;/h5-14,30H,3-4,15-16H2,1-2H3,(H,25,29)(H,26,28);1H;1H2
Chemical Name
[6-(diethylaminomethyl)naphthalen-2-yl]methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate;hydrate;hydrochloride
Synonyms
ITF 2357; ITF2357; ITF-2357; Givinostat; gavinostat; ITF2357 HCl; ITF2357 hydrochloride; Givinostat HCl
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~95 mg/mL (~199.6 mM)
Water: <1 mg/mL
Ethanol: ~3 mg/mL (~6.3 mM)
Solubility (In Vivo)
30% propylene glycol, 5% Tween 80, 65% D5W: 30mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.1010 mL 10.5049 mL 21.0097 mL
5 mM 0.4202 mL 2.1010 mL 4.2019 mL
10 mM 0.2101 mL 1.0505 mL 2.1010 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Biological Data
  • Givinostat (ITF2357)

  • Givinostat (ITF2357)

    Effects of oral ITF2357 on STZ-induced β-cell toxicity, serum nitric oxide levels and spleen cell responses in vivo.Mol Med.2011May-Jun;17(5-6):369-77.

  • Givinostat (ITF2357)

    Effect of HDAC inhibition on cytokine-induced INS-1 cell death.Mol Med.2011May-Jun;17(5-6):369-77.

  • Givinostat (ITF2357)
  • Givinostat (ITF2357)

    ITF2357 protects from cytokine-induced islet injury in vitro.Mol Med.2011May-Jun;17(5-6):369-77.

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